Abstract
The generation and release of membrane-enclosed packets from cancer cells, called extracellular vesicles (EVs), play important roles in propagating transformed phenotypes, including promoting cell survival. EVs mediate their effects by transferring their contents, which include specific proteins and nucleic acids, to target cells. However, how the cargo and function of EVs change in response to different stimuli remains unclear. Here, we discovered that treating highly aggressive MDAMB231 breast cancer cells with paclitaxel (PTX), a chemotherapy that stabilizes microtubules, causes them to generate a specific class of EV, namely exosomes, that are highly enriched with the cell survival protein and cancer marker, Survivin. Treating MDAMB231 cells with a variety of other chemotherapeutic agents, and inhibitors that block cell growth and survival, did not have the same effect as PTX, with the exception of nocodazole, another inhibitor of microtubule dynamics. Exosomes isolated from PTX-treated MDAMB231 cells strongly promoted the survival of serum-starved and PTX-treated fibroblasts and SKBR3 breast cancer cells, an effect that was ablated when Survivin was knocked-down from these vesicles using siRNA. These findings underscore how the enrichment of a specific cargo in exosomes promotes cell survival, as well as can potentially serve as a marker of PTX resistance.
Highlights
Breast cancer remains one of the most prevalent forms of cancer, with one in eight women being diagnosed with invasive breast cancer in their lifetime [1]
We discovered that treating the aggressive MDAMB231 breast cancer cell line with PTX causes them to generate exosomes that are highly enriched with Survivin, a protein whose expression is tightly correlated with poor patient prognosis, chemotherapy resistance, and tumor recurrence [21,22,23,24]
We began by determining the amount and size of exosomes that are inherently generated by the triple negative MDAMB231 breast cancer cell line
Summary
Breast cancer remains one of the most prevalent forms of cancer, with one in eight women being diagnosed with invasive breast cancer in their lifetime [1]. Therapy resistance and tumor recurrence frequently occurs. There continues to be an overriding need to better understand the mechanisms underlying therapy resistance. There are several ways that cancer cells have been shown to overcome the cytotoxic effects of chemotherapy [1]. One such mechanism that is starting to attract a good deal of attention involves the ability of cancer cells to generate and release membrane-enclosed packages, collectively referred to as extracellular vesicles (EVs), that contain a wide-range of protein types including cell surface receptors, cytosolic signaling proteins, metabolic enzymes, cytoskeletal components, and nuclear proteins [2,3,4]. EVs have been shown to contain RNA transcripts, micro-RNAs, and even long non-coding RNAs [5,6,7]
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